Anandamide, the naturally occurring amide of arachidonic acid with ethanolamine, meets all key criteria of an endogenous cannabinoid substance (Devane, W. A. et al. Science, 258, 1946-1949 (1992)): it is released upon demand by stimulated neurons (Di Marzo, V. et al., Nature, 372, 686-691 (1994); Giuffrida, A. et al., Nat. Neurosci., 2, 358-363 (1999)); it activates cannabinoid receptors with high affinity (Devane, W. A. et al. Science, 258, 1946-1949 (1992)) and it is rapidly eliminated through a two-step process consisting of carrier-mediated transport followed by intracellular hydrolysis (Di Marzo, V. et al., Nature, 372, 686-691 (1994); Beltramo, M. et al., FEBS Lett., 403, 263-267 (1997)). Anandamide hydrolysis is catalyzed by the enzyme fatty acid amide hydrolase (FAAH), a membrane-bound serine hydrolase (Cravatt, B. F. et al., Nature, 384, 83-87 (1996); Patricelli, M. P. et al., Biochemistry, 38, 9804-9812 (1999)) (WO 98/20119) (U.S. Pat. No. 6,271,015) that also cleaves other bioactive fatty ethanolamides, such as oleoylethanolamide (cis-9-octadecenamide)) (Rodríguez de Fonseca, F. et al. Nature, 414, 209-212 (2001)) and palmitoylethanolamide (Calignano, A. et al., Nature, 394, 277-281 (1998)). Mutant mice lacking the gene encoding for FAAH cannot metabolize anandamide (Cravatt, B. F. et al., Proc. Natl. Acad. Sci. U.S.A., 98, 9371-9376 (2001)) and, though fertile and generally normal, show signs of enhanced anandamide activity at cannabinoid receptors, such as reduced pain sensation (Cravatt, B. F. et al., Proc. Natl. Acad. Sci. U.S.A., 98, 9371-9376 (2001)). This suggests the possibility that drugs targeting FAAH may heighten the tonic actions of anandamide, while possibly avoiding the multiple, often unwanted effects produced by Δ9-THC and other direct-acting cannabinoid agonists (Hall, W., et al., Lancet, 352, 1611-1616 (1998); Chaperon, F., et al., Crit. Rev. Neurobiol., 13, 243-281 (1999)).
Pain perception can be effectively controlled by neurotransmitters that operate within the CNS. This modulation has been well characterized in the dorsal horn of the spinal cord, where impulses carried by nociceptive (pain-sensing) fibers are processed before they are transmitted to the brain. In addition to these central mechanisms, intrinsic control of pain transmission can occur at terminals of afferent nerve fibers outside the CNS. One prominent example of peripheral regulation is provided by the endogenous opioids, which are released from activated immune cells during inflammation and inhibit pain initiation by interacting with opioid receptors localized on sensory nerve endings1,2.
It has been proposed that endocannabinoid mediators might serve an analogous function to that of the opioids, because pharmacological activation of peripheral CB1 and CB2 cannabinoid receptors inhibits pain-related behaviors3-7 while genetic disruption of CB1 receptor expression in primary nociceptive neurons exacerbates such behaviors8. Moreover, there is evidence that clinical conditions associated with neuropathic pain or inflammation, such as complex regional pain syndrome and arthritis, may be accompanied by peripheral elevations in the levels of the endocannabinoid anandamide9,10. Another major endocannabinoid ligand, 2-arachidonoylglycerol (2-AG), has also been implicated in nociceptive signaling outside the CNS8,11.
Much attention has been directed toward the role of anandamide in pain. Methods of treating pain by administering anandamide and palmitoylethanolamide are disclosed in U.S. Patent Application Publication No.: 20020173550. Methods of treating pain by administering inhibitors of FAAH are disclosed in U.S. Patent Application Publication Nos. 20040127518 and 20030134894. Methods of treating pain by administering inhibitors of anandamide transport are disclosed in U.S. Patent Application Publication No. 20030149082.
Although these findings suggest that the endocannabinoid system serves an important function in the peripheral regulation of nociception, they offer no definitive insight on the identity of the endogenous ligand, or ligands, involved in this function. Thus there exists a need related to an understanding, at a molecular level, of the intrinsic mechanisms that control pain initiation in order to identify new analgesic agents devoid of central side effects. Surprisingly, the present invention satisfies this as well as many other needs by identifying, characterizing, and making brain-impermeant inhibitors of the anandamide-degrading enzyme, FAAH, with the aim of magnifying the actions of peripheral anandamide and unmasking their possible role in the control of emerging pain signals12. Another need in the field of developing and therapeutically using FAAH inhibitors is related to the ability of these inhibitors to modulate endogenous cannabinoid systems within the CNS system to cause unwanted psychotropic or mood-altering effects. The present invention also surprisingly satisfies these and other needs by providing peripherally restricted FAAH inhibitors and methods of their use in the treatment of a variety of conditions, including pain and/or inflammation.
The following references may provide background information for the field to which the present invention pertains. The disclosure of each reference is hereby incorporated by reference in its entirety for all purposes. (1) Stein, C., Schafer, M., & Machelska, H., Attacking pain at its source: new perspectives on opioids. Nat Med 9 (8), 1003-1008 (2003); 2) Stein, C. & Zollner, C., Opioids and sensory nerves. Handb Exp Pharmacol (194), 495-518 (2009); 3) Calignano, A., La Rana, G., Giuffrida, A., & Piomelli, D., Control of pain initiation by endogenous cannabinoids. Nature 394 (6690), 277-281 (1998); 4) Jaggar, S. I., Sellaturay, S., & Rice, A. S., The endogenous cannabinoid anandamide, but not the CB2 ligand palmitoylethanolamide, prevents the viscero-visceral hyper-reflexia associated with inflammation of the rat urinary bladder. Neurosci Lett 253 (2), 123-126 (1998); 5) Nackley, A. G., Suplita, R. L., 2nd, & Hohmann, A. G., A peripheral cannabinoid mechanism suppresses spinal fos protein expression and pain behavior in a rat model of inflammation. Neuroscience 117 (3), 659-670 (2003); 6) Dziadulewicz, E. K. et al., Naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone: a potent, orally bioavailable human CB1/CB2 dual agonist with antihyperalgesic properties and restricted central nervous system penetration. J Med Chem 50 (16), 3851-3856 (2007); 7) Anand, P., Whiteside, G., Fowler, C. J., & Hohmann, A. G., Targeting CB2 receptors and the endocannabinoid system for the treatment of pain. Brain Res Rev 60 (1), 255-266 (2009); 8) Agarwal, N. et al., Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors. Nat Neurosci 10 (7), 870-879 (2007); 9) Kaufmann, I. et al., Enhanced anandamide plasma levels in patients with complex regional pain syndrome following traumatic injury: a preliminary report. Eur Surg Res 43 (4), 325-329 (2009); 10) Richardson, D. et al., Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis. Arthritis Res Ther 10 (2), R43 (2008) 11) Mitrirattanakul, S. et al., Site-specific increases in peripheral cannabinoid receptors and their endogenous ligands in a model of neuropathic pain. Pain 126 (1-3), 102-114 (2006); 12)
Schlosburg, J. E., Kinsey, S. G., & Lichtman, A. H., Targeting fatty acid amide hydrolase (FAAH) to treat pain and inflammation. AAPS J 11 (1), 39-44 (2009); 13) Kathuria, S. et al., Modulation of anxiety through blockade of anandamide hydrolysis. Nat Med 9 (1), 76-81 (2003); 14) Piomelli, D. et al., Pharmacological profile of the selective FAAH inhibitor KDS-4103 (URB597). CNS Drug Rev 12 (1), 21-38 (2006); 15 Clapper, J. R. et al., A second generation of carbamate-based fatty acid amide hydrolase inhibitors with improved activity in vivo. ChemMedChem 4 (9), 1505-1513 (2009); 16) Alexander, J. P. & Cravatt, B. F., Mechanism of carbamate inactivation of FAAH: implications for the design of covalent inhibitors and in vivo functional probes for enzymes. Chem Biol 12 (11), 1179-1187 (2005); 17) Loscher, W. & Potschka, H., Blood-brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRx 2 (1), 86-98 (2005); 18) Cravatt, B. F. et al., Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci USA 98 (16), 9371-9376 (2001); 19) Starowicz, K., Nigam, S., & Di Marzo, V., Biochemistry and pharmacology of endovanilloids. Pharmacol Ther 114 (1), 13-33 (2007); 20) LoVerme, J., La Rana, G., Russo, R., Calignano, A., & Piomelli, D., The search for the palmitoylethanolamide receptor. Life Sci 77 (14), 1685-1698 (2005); 21) Sagar, D. R., Kendall, D. A., & Chapman, V., Inhibition of fatty acid amide hydrolase produces PPAR-alpha-mediated analgesia in a rat model of inflammatory pain. Br J Pharmacol 155 (8), 1297-1306 (2008); 22) Coderre, T. J. & Melzack, R., The contribution of excitatory amino acids to central sensitization and persistent nociception after formalin-induced tissue injury. J Neurosci 12 (9), 3665-3670 (1992); 23) Puig, S. & Sorkin, L. S., Formalin-evoked activity in identified primary afferent fibers: systemic lidocaine suppresses phase-2 activity. Pain 64 (2), 345-355 (1996); 24) Bennett, G. J. & Xie, Y. K., A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33 (1), 87-107 (1988); 25) Ahluwalia, J., Yaqoob, M., Urban, L., Bevan, S., & Nagy, I., Activation of capsaicin-sensitive primary sensory neurones induces anandamide production and release. J Neurochem 84 (3), 585-591 (2003); 26) Liu, J. et al., A biosynthetic pathway for anandamide. Proc Natl Acad Sci USA 103 (36), 13345-13350 (2006); 27) Hohmann, A. G. & Herkenham, M., Localization of central cannabinoid CB1 receptor messenger RNA in neuronal subpopulations of rat dorsal root ganglia: a double-label in situ hybridization study. Neuroscience 90 (3), 923-931 (1999); 28) Hohmann, A. G. & Herkenham, M., Cannabinoid receptors undergo axonal flow in sensory nerves. Neuroscience 92 (4), 1171-1175 (1999); 29) Richardson, J. D., Kilo, S., & Hargreaves, K. M., Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain 75 (1), 111-119 (1998); 30) Mackie, K., Cannabinoid receptors as therapeutic targets. Annu Rev Pharmacol Toxicol 46, 101-122 (2006); 31) LoVerme, J. et al., Rapid broad-spectrum analgesia through activation of peroxisome proliferator-activated receptor-alpha. J Pharmacol Exp Ther 319 (3), 1051-1061 (2006); 32) Guindon, J. & Hohmann, A. G., Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain. Br J Pharmacol 153 (2), 319-334 (2008); 33) Cravat, B. F. et al., Functional disassociation of the central and peripheral fatty acid amide signaling systems. Proc Natl Acad Sci USA 101 (29), 10821-10826 (2004); 34) Lever, I. J. et al., Localization of the endocannabinoid-degrading enzyme fatty acid amide hydrolase in rat dorsal root ganglion cells and its regulation after peripheral nerve injury. J Neurosci 29 (12), 3766-3780 (2009); 35) Tegeder, I. et al., Peripheral opioid analgesia in experimental human pain models. Brain 126 (Pt 5), 1092-1102 (2003); 36) King, A. R. et al., URB602 inhibits monoacylglycerol lipase and selectively blocks 2-arachidonoylglycerol degradation in intact brain slices. Chem Biol 14 (12), 1357-1365 (2007); 37) Astarita, G., Ahmed, F., & Piomelli, D., Identification of biosynthetic precursors for the endocannabinoid anandamide in the rat brain. J Lipid Res 49 (1), 48-57 (2008); 38) Fegley, D. et al., Characterization of the fatty acid amide hydrolase inhibitor cyclohexyl carbamic acid 3′-carbamoyl-biphenyl-3-yl ester (URB597): effects on anandamide and oleoylethanolamide deactivation. J Pharmacol Exp Ther 313 (1), 352-358 (2005); 39) Cadas, H., di Tomaso, E., & Piomelli, D., Occurrence and biosynthesis of endogenous cannabinoid precursor, N-arachidonoyl phosphatidylethanolamine, in rat brain. J Neurosci 17 (4), 1226-1242 (1997); 40) Hargreaves, K., Dubner, R., Brown, F., Flores, C., & Joris, J., A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32 (1), 77-88 (1988).